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Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.

The Akt family of serine/threonine-directed kinases promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins. Here we describe a novel functional interaction between Akt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase. Akt decreased ASK1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus Akt site at serine 83 of ASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway also inhibited the serum deprivation-induced activity of endogenous ASK1 in L929 cells. An association between Akt and ASK1 was detected in cells by coimmunoprecipitation. Phosphorylation by Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activating transcription factor 2 activities in intact cells. Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 in a manner dependent on phosphorylation of serine 83 of ASK1. These results provide the first direct link between Akt and the family of stress-activated kinases.

Pubmed ID: 11154276


  • Kim AH
  • Khursigara G
  • Sun X
  • Franke TF
  • Chao MV


Molecular and cellular biology

Publication Data

February 6, 2001

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS21072

Mesh Terms

  • Amino Acid Sequence
  • Apoptosis
  • Cell Line
  • Cell Survival
  • HeLa Cells
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP Kinase Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt
  • Serine
  • Signal Transduction
  • Substrate Specificity